2-substituted-4-propargyloxymethyl-ypsilon-butyrolactones

ABSTRACT

A COMPOUND OF THE FORMULA:   2-(O=),3-R,5-(HC*C-CH2-O-CH2-)TETRAHYDROFURAN   IN WHICH R IS HYDROGEN, ALKYL HAVING 1 TO 10 CARBON ATOMS ARYL ALIPHATIC IN WHICH THE ARYL CAN BE SUBSTITUTED BY ONE OR MORE HALOGENS, ONE OR MORE ALKOXY, ALIPHATIC HAVING 1 TO 4 CARBON ATOMS OR TRIFLUOROMETHYL. THE COMPOUND IS FORMED BY SAPONIFYING AND THEN DECARBOXYLATING THE CORRESPONDING 2-ETHOXYCARBONYL DERIVATIVE. THE COMPOUNDS POSSESS ANXIOLYTIC, ANTI-DEPRESSIVE, ANALGESIC AND RESPIRATORY STIMULATING PROPERTIES.

*fluoromethyl'radical. e The process according to the present inventioncom rprises saponifying and then decarboxylating a 4-pr0par distilledunder reduced pressure.

United States Patent 3,755,370 2-SUBSTITUTED 4-PROPARGYLOXY1WETHYL--BUTYROLACTONES Claude P. Fauran, Guy M. Raynaud and Colette A.

Douzon, Paris and Janine M. Thomas, Neuilly-sur- Seine, France,assignors toDelalande S.A., Courbevoie,

France No Drawing. Filed Aug. 22, 1969, Ser. No. 852,476 Claimspriority, applicationa Ggat Britain, Sept. 17, 1968,

4 0' v, Int. (:1. 607a 5/06 US. Cl. 260343.6 4 Claims ABsrRAcT O F THEDISCLOSURE A compound of theformula:

in which R is hydrogen, alkyl having 1 to carbon atoms or aryl aliphaticin which the aryl can be su'bsti: tuted by one or more halogens, one ormore alkoxy, aliphatic having 1 to 4 carbon atoms or trifluoromethyl.The compound is formed by sa'ponifying and then deearboxyraang'tnecorresponding "2-ethoxyca'rbonyl deriva= tive. The compounds possessanxiolytic, anti-depressive, analgesic and respiratory. stimulatingproperties.

The present invention concerns new 4-propargyloxy-' methyl-'-butyrolactones, their process of preparation, and their therapeuticapplication. n

The compounds according to the present-.iuyentio correspond'to theGeneral'For'muIaI' HCEC-CHj-O-CHUO in which R represents a hydrogenatompan alkyl chain... having l te-1O carbon atoms, oran arylaliphaticradical,..

the. aryl part of which being optionally substituted by one or morehalogen atoms, one or more alkoxy radicals, an aliphatic radical having1 to 4 carbon atomsor a trigyloxymethyl-Z-ethoxycarbonyl 'ybutyrolactone of the Formula II o HcEo-om-o-om-Uo v FCQOGZHE.

3,755,370 Patented Aug. 28, 1973 Boiling point=135 C. under 0.1 mm. HgYield=% Elementary analysis.-Calculated (percent: C, 62.32; H, 6.54.Found (percent): C, 62.12; H, 6.64.

EXAMPLE 2 4-proparglyoxymethyl-2-methyl--y-butyrolactone Elementaryanalysis.-Calculated (percent): C, 64.27; H, 7.19. Found (percent): C,64.11; H, 7.39.

EXAMPLE 3 4-propargyloxymethyl-2-n-butyl- -butyrolactone This compoundis obtained according to the procedure described in Example 1 exceptthat 4-propargyloxymethyl-Z-n-butyl-Z-ethoxycarbonyl 'y butyrolactone isused instead of 4 propargyloxymethyl-2-ethoxycarbonylw-butyrolactone.

Boiling point=155 C. under 0.05 mm. Hg Yield=90% Elementaryanalysis.Calculated (percent): C, 68.54; H, 8.63. Found (percent): C,68.56; H, 8.58.

EXAMPLE 4 4-propargyloxymethyl-2-benzyl-y-butyrolactone To a 10% sodasolution heated to 80 C. there is introduced 31 g. of 4propargyloxyrnethyl- 2 benzyl-2- ethoxycarbonyl-y-butyrolactone. After45 minutes of contact at the same temperature with agitation, themixture is cooled and then acidified with hydrochloric acid. The

,7 organic product'salting out is extra cted wyith ethe ig Aftc rdecantation and concentration of the organic"phase, the

"The following preparations are given as non-limitative examples toillustrate the present invention.

7 i QEXAMPTQE I v n 4-propargyloxymethyl-'y-butyrolactoinep;

To a 20% soda 8511mm heated to 35 C.,. ther'e"is progressivelyintroduced, with agitation, 34f 'gf"'of 4-propargyloxymethyl -2ethoxycarbonyl :y. "butyr 1actone whilst avoiding an increase intemperature to alibi/e40 C. When. the dissolutionis complete, themixtureis cooled and acidified with dilute' hydrochloric-e acid.Thegoily pr d a t naput,issx rastsd.w thnsthereffheresiiue obtained byconcentration is heated to 100 and then Yield=73% product obtained isheated to C. until the evolution of carbon dioxide gas has ceased. Theare distilled under reduced pressure.

Boiling point= 170. o. under 0.04

Elmeriiz'iiy ahalysz'sI CalculatedTpercent)i C: 73175; H, 6.60. Found(percent) C, 73.78, H,- 6.75.

m hyl eeh aq ez wt e em? :This'eom oundis obtained according tethe proedure described Example 7 4' except that =4-propargyloxy'inethyl-2-p-chlorobenzyl-2-ethoxycarbonyl -1 a1 butyrolactone is usedf.

i Yield=70% Elementary aiuilysia-Calculated (percent): C, 64.63; H,5.42;-C1, 12.72. Found (percent): C,"64:51'; H, 5.29; (11,1255. 7.. -1

EXAMPLE 6 By way of example, the results obtained with three of 4Pmpargyloxymethyl z p methoxybenzyl ,y %ebclompounds of general FormulaI are given in Table butyrolactone e This compound is obtained accordingto the procedure V T BLE' described in Example 4 except that4-propargyloxy- 1 Dose' methyl-2-p-methoxybenzyl-Z-ethoxycarbonyl 7butyroadminislactone is used. R I fg; ga: Boiling point=205 0. under 0.2mm. Hg 10 Yield=63% 50 Elementary analysis.Calculated (percent): C,70.05; 100 as H, 6.61. Found (percent): 0, 70.09; H, 6.85. writ-@411EXAMPLE 7 100 40 4-propargyloxymethyl-Z-p-fluorobenzyl-v-butyrolactone15 V This compound is obtained according to the procedure described inExample 4 except that 4-propargyloxymethyl-Z-p-fluorobenzyl-2-ethoxycarbonyl-v-butyrolactone is used.

Boiling point=185190 C. under 0.06 mm. Hg In the anaesthetisedguinea-pig, whose respiration has Yield=83% been depressed by anintravenous injection of morphine, Elementary analysis.-Calculated(percent): C, 68.69; the administration of the compounds of GeneralFormula H, 5.77. Found (percent): C, 68.49; H, 5.88. I exerts afavourable effect on the respiratory rhythm and The compounds accordingto the present invention have amplitude.

been studied on animals in the laboratory and have been For example,theresults obtained with two of the com- (4) Stimulant properties shownto possess, inparticular, anxiolytic, anti-depressive, pounds of GeneralFormula I are given in Table III analgesic and respiratory stimulatingproperties. below:

(I) Anxiolytic properties TABLE m The oral administration of thecompounds of the Gen- 1 Dose Increase Increase eral Formula I accordingto the present invention exercise 1 V istered, plratory piratory anopposite antagonism to the mortal convulsions promgykgy rhythm,amplitude, voked by the injection of pentetradol or strychnine in Rpercent percent mice, an improvement in the performance of mice in the10 130 40 electric shock test having an enclosure surrounded by 20 16090 four electrically conductive plates and an increase in the 10 70motivity measured in mice by an actimeter having a pencil H of rays andphoto-electric cells or by the evasion test on an inclined plane, or, inrats in open field with appraise- 40 ment of crossed furrows and thenumber of setting up of As is shown by the results given above and thoseof the animal. Table IV below,-the difierence between the pharmacolo-The results obtained with a certain number of comgically active dose andthe lethal dose is sufliciently great pounds in accordance with theinvention are shown in to allow the compounds of General Formula I to beused Table I below: therapeutically.

TABLE I Motivity at,- l V Protection against- 4 Increase in the numbervof- Electiieshock R I p T I Pentetrazol Strychnine test "ActimetrlcEvasion Settlngup -Crossediurrows .t Y 'Efieetzfio Efiectfio? Increaseof7 Increase 40% Increase of70% 30% at 200 40% 9.12200 CHzat 230 132.!it 33 mgf/ at; mgJk. at 100 mgJkg. at 200 mg.[kg. mg./kg. mgJkg. l, r

(2) Anti-depressive properties I r TABLE IV The oral administration ofthe compounds of General 60 V g p p Dgf fg Formula I causes a notablereduction of the ptosis and man ity, hypothermia caused by reserpine inmice and gastric ulcers a R r I Animal l g-I e percent caused by thesame compound in rats. a. 000 50 -Forexample, the results obtained with4-propargy1oxymethyl-Z-benyl-y-butyrolactone are as follows: 1.000 50 At100 mg./kg./p.o.,-this compoundinhibits the ptosic and hypothermicefiects caused by reserpine in mice, and at mg./kg./p.o., it protects50% of the rats against -39 1 the ulcerogenic action of this compound. 1r l (3) Analgesic properties These properties shown themselves by aninhibition of the painful stretchings provoked by the inter-peritonealinjection of acetic acid in mice.

75 tered to treat anxiety neuroses, depressive syndromes,

pains and aches of different sorts and respiratory insufiiciencies.

They are given in the form of tablets and suppositories containing 25 to100 mg. of active ingredient, drops and syrups containing 1% to 10% ofactive ingredient or injectable ampoules containing 10 to 200 mg. ofactive ingredient.

The starting materials for the processes described above can be preparedby the processes described in U.S. patent applications Ser. No. 851,757,filed Aug. 20, 1969, by Claude P. Fauran, Guy M. Raynaud, Colette A.Douzon and Claude J. Gouret, now U.S. Pat. No. 3,663,572 and Ser. No.852,086, filed Aug. 21, 1969, by Claude P. Fauran, Guy M. Raynaud,Colette A. Douzon and Bernard M. Pourrias, now U.S. Pat. No. 3,665,014.

What We claim is:

1. A compound of the formula:

6 in which R is selected from the group consisting of hydrogen, alkyl ofthe formula C H in which n is from 1 to 4, benzyl, and substitutedbenzyl in which the benzene ring has a substituent selected from thegroup consisting of halogen and lower methoxy.

2. A compound as defined in claim 1, in which R is hydrogen.

3. A compound as defined in claim 1, in which R is methyl or n-butyl.

4. A compound as defined in claim 1, in which R is benzyl,p-chlorobenzyl, p-methoxybenzyl or p-fiuorobenzyl.

References Cited Wagner and look: Synthetic Organic Chemistry, Wiley andSons, N.Y., 1953, p. 416-417 and 838 relied on.

DONALD G. DAUS, Primary Examiner A. M. T. TIGHE, Assistant Examiner U.S.C1. X.R. 424-279 UNETED STATES MTENT FFECE CERTiFiCATE 0F CQRRECTWNPatent No. 3 755 370 Dated Auggst 28 1973 I Claude P. Fauran, Guy M.Raynaud, Colette A. Douzon and Janine M. Thomas It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 6, line 5 before "methoxy" delete lower--.

Signed and sealed this 19th day of February 197).

(SEAL) Attest: V

EDWARD M.FLETCHER;JR. c. MARSHALL DANN Attesting Officer Commissioner ofPatents ORM PO-105O (10-69) USCOMM-DC 60s76-P69 a u.s, GOVIRNMINTPRINTING orllclx I9" o-ul-sal.

